Restoration of the Microbiome Through Superdonor Selection (RESTORE-UC)

Fecal Microbiota Transplantation in Patients With Active Ulcerative Colitis: Restoration of the Microbiome Through Superdonor Selection

The AIM of this study is to investigate whether the FMT success rate in active UC patients can be increased by intensive donor pre-screening, anaerobic preparation of the FMT and by repeated FMT.

The investigators will start a national multi-centre double-blind randomized sham-controlled trial in April 2017 at 6 hospitals in Belgium and 2 in The Netherlands. They will randomly allocate 108 patients with active ulcerative colitis (Mayo score 4-10, endoscopic Mayo score 2 or 3) in a 1:1 ratio, using a pre-established randomization list, to either 'superdonor' faecal microbiota transplantation or autologous fecal microbiota transplantation (=sham). Each patient will receive 4 FMT's. At baseline FMT will be performed during sigmoidoscopy. At week 1, 2 and 3, the FMT will be administered through rectal instillation. Each FMT will be derived from one donor. Donors will be pre-selected based on a species richness and abundance of taxa of interest. The primary outcome will be steroid-free clinical and endoscopic remission at week 8 (Mayo score ≤2, all subscores ≤ 1, and ≥1 point reduction in endoscopy subscore). Fecal, blood and mucosal samples and questionnaires will be collected at different time points. 16S rRNA stool analysis will be performed to assess the microbial changes after FMT.

Study Overview

• Status: Unknown
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Other: superdonor FMT; Other: autologous FMT

Detailed Description

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease (IBD) characterized by a diffuse mucosal inflammation, extending proximally from the rectum and causing symptoms of bloody diarrhea. The complex pathogenesis of IBD remains largely unknown.

Manipulation of the enteric microbiota to restore normobiosis has therapeutic potential in IBD. Fecal microbiota transplantation (FMT), whereby fecal microbiota from a healthy donor is transplanted to a patient, is being studied as therapy for active UC patients. Currently three randomized controlled FMT trials have been published in patients with active ulcerative colitis with increasing success9-11. The investigators feel that the FMT success rate in active UC patients can be improved by solving the remaining pressing questions including the use of selected donors, preparation of the FMT, mode and frequency of administration. The investigators therefore designed a new multicenter interventional study with FMT to specifically answer these questions.

The overall main aims of this project are:

Objective 1: They want to examine whether the FMT success rate in active UC patients can be increased by strictly pre-selecting the donors, by standardizing and optimizing the FMT preparation and by repeated FMT administration.

Objective 2: The investigators want to investigate the temporal and functional changes of the intestinal microbiota of UC patients after FMT

Objective 3: They will try to define host-related predictors for (non-)response to FMT with integration of the genetic susceptibility of the patients and their baseline mucosal gene expression

Study design:

This will be a national multicenter (6 university centers) double blind placebo-controlled randomized clinical trial to evaluate the efficacy and safety of FMT in active UC patients (Mayo endoscopic sub score: 2 or 3 and Total Mayo score: 4-10).

The primary endpoint will be steroid-free clinical and endoscopic remission at week 8 (defined as a total Mayo score of 2 or less, with all Mayo subscores of 1 or less, and at least a 1 point reduction from baseline in the endoscopy subscore).

The secondary endpoints will be the investigation of changes in blood and fecal inflammatory markers before and after FMT (e.g. calprotectin and C-reactive protein (CRP)), steroid-free clinical remission, steroid-free clinical response, steroid-free endoscopic remission and steroid-free endoscopic response.

Assuming a success rate of 40% to achieve mucosal healing at week 8 in the donor FMT arm, a treatment difference of 25% in the autologous FMT arm, a sample size of 49 patients per group is required to obtain a power of 80% and a statistical significance at the 5% level. In addition, considering 10% dropouts, a total of 108 patients will be included. Two interim analysis will be performed after inclusion of respectively 33% and 66% of the sample size (N=108) at week 8.

A data and safety monitoring board (DSMB) can than give advice on adjustment of the sample size or early termination.

Fecal, blood, mucosal samples and questionnaires will be collected by the investigators at different time points.

Baseline fecal samples from donors and baseline mucosal samples together with fecal samples (at start of the study and at weeks 0, 1, 2, 3, 4, 8, 12, 24, 52) from patients will be studied by 16S rDNA sequencing based analysis of microbiota.

The goal of the investigators is to improve FMT success rates by microbial prescreening of the donor and by repeated FMT (4 FMT's/patient).

Prior to FMT, donor stool and blood will be screened for pathogens according to the international consensus guidelines. Furthermore, the investigators will pre-select their donors based on species richness and abundance of taxa of interest.

One donor per ten patients will be used and fecal material will be frozen at -80° until use. Therefore the investigators need at least 15 donors to provide fecal samples during the whole trial, inclusive the open-label faze ( +/- 600 donor samples in total).

To optimize the FMT preparation the investigators will prepare the FMT samples under strict anaerobic circumstances.

To standardize the FMT preparation an absolute cell count of the fecal suspension will be determined after a first dilution.

Repeated FMT will be performed for four times with an interval of 1 week until week 4. At baseline, patients will drink 2L Moviprep (standard preparation), afterwards a sigmoidoscopy will be performed whereby the donor feces solution will be administered through a rectal tube.

At week 1, 2 and 3, the donor feces solution will be administered through rectal instillation without prior water enema.

Open label FMT will be available for all patients in the sham-FMT arm from week 8.

• Study Type: Interventional
• Enrollment (Anticipated): 108
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Clara Caenepeel, MD; Phone Number: +32 16 32 51 48; Email: clara.caenepeel@kuleuven.be
• Study Contact Backup: Name: Jolien Lefrère; Phone Number: +32 16 34 88 56; Email: jolien.lefrere@uzleuven.be

Study Locations

• Belgium
  • Vlaams Brabant
    • Leuven, Vlaams Brabant, Belgium, 3010
      • Recruiting
      • UZ Leuven
      • Contact: Clara Caenepeel, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age >18 years
• Patients with currently mild-moderate active ulcerative colitis (defined by endoscopic Mayo sub score 2-3 and a Total Mayo score between 4-10)
• Provide written informed consent to participate as shown by a signature on the consent form.

• Patients on concomitant UC-therapy are allowed if the concomitant treatment is restricted to current treatment and at a stable dose (not in the induction faze).

  • Topical therapy and trial medication is not allowed.
  • A maximum dose of 15mg methylprednisolone.
• Negative coproculture (Salmonella, Shigella, Yersinia, Campylobacter, Entamoeba histoliytica, Clostridium difficile toxins and enteropathogenic E. coli)
• Women need to use reliable contraceptives during participation in the study

Exclusion Criteria:

• Consent not obtained or unable to give informed consent

• Condition leading to profound immunosuppression

  • For example: HIV, infectious diseases leading to immunosuppression, bone marrow malignancies, liver cirrhosis
  • Use of systemic chemotherapy
• Use of antibiotics in the previous 4 weeks
• Surgery: Total colectomy, presence of a stoma or ileo-anal pouch
• Presence of an intra-abdominal fistula
• Colon carcinoma
• Diverticulitis
• Patients who are steroid dependent and requiring >15mg methyl prednisone 2 week before START.
• Detection of a gastrointestinal pathogen on stool analysis
• A diagnosis of Crohn's disease of indeterminate colitis
• Females who are pregnant or actively trying to fall pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Superdonor FMT; Fecal microbiota transplantation from a healthy donor that was selected based on a fecal/blood screening, medical interview and on abundance of taxa of the investigators their interest	Other: superdonor FMT; Fecal microbiota transplantation (FMT) is the transfer of feces from a healthy "superdonor" to the patient.
SHAM_COMPARATOR: Autologous FMT; Fecal microbiota transplantation derived from feces from the patient her/himself.	Other: autologous FMT; Fecal microbiota transplantation (FMT) with feces from the patient him/herself

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
steroid-free clinical remission	defined as a total Mayo score of 2 or less and with all Mayo subscores of 1 or less.	Week 8
steroid-free endoscopic remission or response	defined as at least a 1 point reduction from baseline in the endoscopy subscore.	Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the investigation of changes in blood and fecal inflammatory markers before and after FMT	changes in calprotectin and C-reactive protein (CRP)	Week 8
Steroid-free clinical remission	combined Mayo subscores of 1 or less for rectal bleeding plus stool frequency	Week 8
Steroid-free clinical response	a decrease of 3 points or more on the Mayo score, a 50% or greater reduction from baseline in combined rectal bleeding plus stool frequency Mayo subscores, or both.	Week 8
Steroid-free endoscopic response	Mayo endoscopic subscore of 1 or less, with a reduction of at least 1 point from baseline	Week 8
Steroid-free endoscopic remission	Mayo endoscopy subscore of 0 or 1.	Week 8

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: Fund for Scientific Research, Flanders, Belgium
• Investigators: Principal Investigator: Séverine Vermeire, MD and PhD, UZ Leuven

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 30, 2017
• Primary Completion (ANTICIPATED): April 30, 2019
• Study Completion (ANTICIPATED): April 30, 2019

Study Registration Dates

• First Submitted: March 30, 2017
• First Submitted That Met QC Criteria: April 11, 2017
• First Posted (ACTUAL): April 12, 2017

Study Record Updates

• Last Update Posted (ACTUAL): March 30, 2018
• Last Update Submitted That Met QC Criteria: March 28, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Fecal microbiota transplantation
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: S59525

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No